Clinical management of patients with syphilis is controversial. This article summarizes recent research on syphilis treatment efficacy and outcomes and is based on a comprehensive systematic review of published literature, relevant abstracts, conference proceedings, technical reports, and guidelines. Penicillin remains the drug of choice for the treatment of syphilis. Although several studies have suggested that azithromycin may have clinical efficacy, macrolide resistance has been widely documented among strains of Treponema pallidum, and treatment failures have been reported. Ceftriaxone is effective for the treatment of syphilis when used in multiple-dose regimens. Lumbar puncture should be performed for human immunodeficiency virus-infected patients with syphilis of >1 year's duration and a serum nontreponemal test titer > or =1 : 32, as well for other patients for whom the clinical suspicion of neurosyphilis is high. Newer laboratory tests for syphilis are undergoing extensive evaluation and may prove to be useful for future clinical care. American and European approaches to syphilis treatment are similar, but they vary across several parameters.